Metalloproteinase inhibitors

Abstract

A compound of formula (I): ##STR1## wherein R.sub.4 is an optionally substituted C.sub.3 -C.sub.8 cycloalkenyl group. The compounds are inhibitors of matrix metalloproteinases.

Claims

1. A compound of formula (I):

X is a --CO.sub.2 H or --CONHOH group;

R.sub.1 is hydrogen; (C.sub.1 -C.sub.6)alkyl; (C.sub.2 -C.sub.6)alkenyl; phenyl; substituted phenyl; phenyl (C.sub.1 -C.sub.6)alkyl); substituted phenyl(C.sub.1 -C.sub.6)alkyl; heterocyclyl; substituted heterocyclyl; heterocyclyl(C.sub.1 -C.sub.6)alkyl; substituted heterocyclyl(C.sub.1 -C.sub.6)alkyl; a group BSO A-- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6) alkyl, phenyl, substituted phenyl, heterocyclyl, (C.sub.1 -C.sub.6)acyl, phenacyl or substituted phenacyl group, and A represents (C.sub.1 -C.sub.6)alkyl; amino; protected amino; acylamino; OH; SH; (C.sub.1 -C.sub.6)alkoxy; (C.sub.1 -C.sub.6)alkylamino; di-(C.sub.1 -C.sub.6)alkylamino; (C.sub.1 -C.sub.6)alkylthio; aryl (C.sub.1 -C.sub.6)alkyl; amino (C.sub.1 -C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated; lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino;

R.sub.2 is a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl heteroaryl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6) alkyl group, any one of which may be optionally substituted by one or more substituents selected from the group consisting of (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, --O-phenyl, --O(C.sub.1 -C.sub.6)alkylphenyl, halo and cyano (--CN);

R.sub.3 is the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected, PROVIDED that R.sub.3 is not a fused or conjugated unsubstituted or substituted bicycloarylmethylene group;

R.sub.4 is an optionally substituted C.sub.3 -C.sub.8 cycloalkyl group or optionally substituted C.sub.4 -C.sub.8 cycloalkenyl group;

R.sub.5 is hydrogen or a (C.sub.1 -C.sub.6)alkyl group; or a salt, hydrate or solvate thereof.

2. A compound as claimed in claim 1 wherein the stereochemistry is as follows:

C atom carrying the R.sub.1 and X groups --S,

C atom carrying the R.sub.2 group --R,

C atom carrying the R.sub.3 group --S.

3. A compound as claimed in claim 1 or claim 2 wherein R.sub.1 is hydrogen, methyl, ethyl, hydroxyl, allyl, thienylsulphanylmethyl, thienylsulphinylmethyl, thienylsulphonylmethyl or phthalimidomethyl.

4. A compound as claimed in claim 1 or claim 2 wherein R.sub.2 iso-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclohexylpropyl, phenylpropyl, 3-phenyl-prop-2-enyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, pyrid-4-ylpropyl, phenylbutyl, benzyloxybutyl, phenoxybutyl, propyloxymethyl and propylsulphanyl.

5. A compound as claimed in claim 1 or claim 2 wherein R.sub.3 is benzyl, iso-butyl, 1-fluoro-1-methylethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, S-benzyl-2-methyl-2-thiopropyl, 1 -mercapto-1 -methylethyl or t-butyl.

6. A compound as claimed in claim 1 or claim 2 wherein R.sub.4 is cyclopropyl, 2-phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

7. A compound as claimed in claim 1 or claim 2 in which R.sub.5 is hydrogen, methyl or ethyl.

9. A process for the preparation of a compound as claimed in claim 1 in which X is a hydroxamic acid group (--CONHOH), which process comprises:

(a) causing an acid of general formula (II) ##STR24## or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, or an N,O-diprotected hydroxylamine, or a salt thereof, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 being as defined in general formula (I) except that any substituents in R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 which are potentially reactive with hydroxylamine, O-protected hydroxylamine, the N,O-diprotected hydroxylamine or their salts may themselves be protected from such reaction, then removing any protecting groups from the resultant hydroxamic acid moiety and from any protected substituents in R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5; or

(b) deprotecting a diprotected hydroxamic acid derivative of formula (IIb) ##STR25## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as defined in general formula (I), R.sub.14 is an amino protecting group and R.sub.15 is a hydroxyl protecting group.

10. A process for the preparation of a compound as claimed in claim 1 in which X is a carboxylic acid group (--COOH) which process comprises coupling an acid of formula (III) or an activated derivative thereof with an amine of formula (IV) ##STR26## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as defined in general formula (I) except that any substituents in R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 which are potentially reactive in the coupling reaction may themselves be protected from such reaction, and R.sub.11, represents a hydroxy protecting group, and subsequently removing the protecting group R.sub.11, and any protecting groups from R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5.

11. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 or claim 2 together with a pharmaceutically or veterinarily acceptable excipient or carrier.

12. A pharmaceutical or veterinary composition as claimed in claim 11 which is adapted for oral administration.